US3594413A - Cyclopentene derivatives - Google Patents

Cyclopentene derivatives Download PDF

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Publication number
US3594413A
US3594413A US777506A US3594413DA US3594413A US 3594413 A US3594413 A US 3594413A US 777506 A US777506 A US 777506A US 3594413D A US3594413D A US 3594413DA US 3594413 A US3594413 A US 3594413A
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Prior art keywords
cyclopentene
dione
reaction
carboxylic acid
oxa
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US777506A
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Harvey E Alburn
Horace Fletcher
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Wyeth LLC
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American Home Products Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

Definitions

  • 1,3-diazaspiro[4,4] nonene-2,4-diones 1,3-diazaspiro[4,4] nonene-2,4-diones; l-aminocyclopentene-l-carboxylic acids; 1-(N-alkylamino)cyclopentene-l-carboxylic acids; and 3-oxa-1-azaspiro[4,4] nonene-2,4-diones which are useful intermediates in the synthesis of 6-(1- aminocyclopentene-l-carboxamido)penicillanic acids.
  • R is selected from the group consisting of carboxy and amido;
  • R is selected from the group consisting of amino, lower alkyla'mino, phen(lower)alkylamino and amido with the proviso that when R is amido R is also amido; and when R and R are taken together with the carbon atom to which they are attached they form a ring selected from the group consisting of 1,3-diazolidin- -yl-2,4-dione, 3-oxa-1-azolidin-5-yl-2,4-dione, l-(lower) alkyl-3-oxa-1-azolidin-5-yl-2,4-dione, and 3-oxa 1 phen- (lower)alkyl-1-azolidin-5-yl-2,4-dione.
  • Typical examples thereof are: 3-cyclopentene-l,l-dicarboxamide; 1,3-diazaspiro[4,4] non-7-ene-2,'4-dione; 1-amino-3-cyclopentene-1- carboxylic acid; and 3-oxa-1-azaspiro[4,4] non-7-ene-2,4- dione.
  • Tl - COOR Amidation CONH; C O O R C O NH;
  • the amidation reaction is effected by contacting a dialkyl cyclopentene-l,l-dicarboxylate (I) with an alkanol saturated with ammonia containing an alkali metal alkoxide for about seventy hours at ambient temperatures. Subsequently, the reaction mixture is admixed with an alkali metal e.g. sodium or potassium in anhydrous alkanol for about an additional forty-eight hours. Preferably this reaction is conducted using ammonia saturated methanol containing sodium methoxide and then sodium in anhydrous methanol.
  • the amidation reaction is complete the resulting cyclopentene-l,l-dicarboxamide (II) is recovered by standard procedures. For example, the insoluble product (II) is filtered, washed with an appropriate solvent e.g. methanol, and then dried.
  • the cyclization (A) reaction is effected by contacting an above-prepared cyclopentene-l,l-dicarboxamide (II) with an aqueous solution of an alkali metal hypohalite at about freezing temperatures and then allowing the resulting solution to warm to ambient temperatures. Preferably this reaction is conducted using an aqueous solution of sodium hypobromite.
  • the resulting 1,3-diazaspiro[4,4] nonene-2,4- dione (III) is recovered by conventional methods e.g. the reaction mixture is acidified with a mineral acid, evaporated to dryness, the residue extracted with an appropriate solvent, such as, hot ethyl acetate, filtered and the filtrate evaporated to dryness.
  • the cleavage reaction is effected by contacting an aboveprepared l,3-diazaspiro[4,4] nonene-2,4-dione (III) with barium hydroxide in water in an autoclave at about 200 C. for a period of about twenty hours. Thereafter, the reaction mixture is dissolved in a dilute mineral acid and admixed with sulfuric acid. When the reaction is complete, the resulting l-aminocyclopentene-l-carboxylic acid (IV) is separated by routine recovery procedures.
  • the reaction mixture is filtered, the filtrate evaporated to dryness, the residue extracted with hot methanol, the extract evaporated and reconstituted with water, the resulting solution passed through a column of a strong acid resin in the hydrogen cycle, the column washed with water and eluted with ammonium hydroxide, the efiluent is evaporated to dryness and the product (IV) crystallized from an appropriate solvent e.g. methanol-ethanol.
  • the alkylation reaction is efiected by contacting an above-prepared 1-aminocyclopentene-l-carboxylic acid (IV) in an aqueous solution of an alkali metal hydroxide with a p-toluenesulfonyl halide, e.g. chloride in a waterimmiscible organic solvent, such as, ether, hexane or benzene at about ambient temperatures for a period of about sixteen hours.
  • a waterimmiscible organic solvent such as, ether, hexane or benzene at about ambient temperatures for a period of about sixteen hours.
  • the water-immiscible organic layer is then discarded, and the aqueous phase acidified with a mineral acid e.g. hydrochloric acid, the resulting precipitate is separated, washed and dried to give a l-toluene-psulfonamidocyclopentenecarboxylic acid.
  • the above-prepared sulfonamide, an alkyl halide, such as, methyl iodide and an aqueous solution of an alkali metal hydroxide e.g. sodium hydroxide are heated at about 100 C. for a period of about three hours. Thereafter, the reaction mixture is cooled, filtered, and the filtrate acidified with a mineral acid to afford an appropriate 1 N-alkyl-toluene-p-sulfonamidocyclopentene carboxylic acid.
  • an alkyl halide such as, methyl iodide
  • an alkali metal hydroxide e.g. sodium hydroxide
  • This N-alkylsulfonamide is heated in concentrated hydrochloric acid in sealed glass tubes at about 150 C. for a period of about ten hours.
  • the reaction is complete, the resulting I-(N-alkylamino)-cyclopentene-1 carboxylic acid (V) is recovered by standard procedures. For example, the reaction mixture is evaporated to dryness, the residue dissolved in water, the solution passed through a column of a strong basic resin in the base cycle, then the efiluent is evaporated and the residue crystallized from a suitable solvent e.g.
  • the cyclization (B) reaction is effected by contacting either a l-aminocyclopentene-l-carboxylic acid (IV) or a l-(N-alkylamino)-cyclopentene-1-carboxylic acid (V) with phosgene in a reaction-inert organic solvent e.g. dioxane, benzene or tetrahydrofuran at a temperature range of about 70 C. to about 80 C. for a period of up to about two hours.
  • a reaction-inert organic solvent e.g. dioxane, benzene or tetrahydrofuran
  • reaction mixture is flushed with an inert gas, such as, nitrogen, the solvent evaporated, the residue dissolved in a suitable solvent e.g. ethyl acetate and then crystallized from an appropriate liquid, such as, hexane.
  • an inert gas such as, nitrogen
  • dialkyl cyclopentene-1,1-dicarboxylate (I) starting materials are prepared by the procedure described by G. Schmid and A. Wolkolf in J. Org. Chem. 32, 254 (1966).
  • the other materials employed in the herein described reactions are commercially available or are easily prepared by procedures which are well known in the chemical art.
  • the new and novel cyclopentene-1,1-dicarboxamides (II); 1,3 diazospiro[4,4] nonene 2,4-diones (III), 1- aminocyclopentene-l-carboxylie acids (IV); l-(N-alkylamino)cyclopentene-l-carboxylic acids (V); and 3-oxa-1- azaspiro[4,4] nonene-2,4-diones (VI) are valuable intermediates in the preparation of biologically active 6-(1- aminocyclopentene 1 carboxamido)penicillanic acids which are described and claimed in copending United States Ser. No.
  • these penicillin compounds are, therefore, of value as antibacterial agents, nutritional supplements in animal feed; agents for the treatment of mastitis in cattle; and as therapeutical agents in poultry and mammals, in the treatment of infectious diseases caused by gram-positive and gram-negative bacteria, upon either parenteral or oral administration. Further, when employed as such these penicillins are significantly less toxic to the recipient host than related prior art compounds.
  • the penicillins which are prepared from the intermediates of this invention when employed in mammals, e.g. mice, rats, dogs, monkeys and the like, they may be administered orally or parenterally. Naturally, the dosage of these compounds will vary somewhat with the form of administration and the particular compound chosen. Furthermore, it will vary with the particular subject under treatment. In general, these penicillin compounds which are prepared from the intermediates of this invention are most desirably administered at a concentration level that is in the range of from about 10 to about 400 mg. per kilo per day, although as aforementioned variations will occur. However, this dosage range will generally afford effective results without causing any harmful or deleterious side effects.
  • the filtrate is diluted with one liter of methanol containing 15 g. of sodium and the solution is resaturated with ammonia and allowed to stand overnight.
  • the clear solution is then evaporated in vacuo to one liter on a rotary evaporator and filtered to afford additional product, (yield 31 g., 20%), MP. 222223 C., for a total yield of 108 g.
  • diethyl-Z-cyclopentene-l,l-dicarboxylate is converted to 2-cyclopentene-1,l-dicarboxamide.
  • EXAMPLE II of ammonium bicarbonate are added and the solution is warmed to 50 C. on a steam bath before acidifying to pH 2 with 12 N hydrochloric acid.
  • the acidified solution is evaporated to dryness, the residue extracted with 500 ml. of hot acetone and then filtered.
  • the filtrate is evaporated to dryness in vacuo and the crude product twice crystallized from 400 ml. of hot water to afford 1,3-diazaspiro[4,4] non-7-ene-2,4-dione, total yield 25.6 g. (53.4%), MP. 190-193 C.
  • N-methyl sulfonamide (17 g., 0.055 mole) is heated in 180 ml. of 12 N hydrochloric acid in sealed glass tubes at 140 C. for eight hours. After cooling, the clear solution is evaporated to dryness under vacuum, the residue dissolved in 300 ml. of water and passed through a column of a strong basic resin in the base cycle, the effluent is evaporated and the residue recrystallized from ethanol to yield 1-methylarnino-3-cyclopentene-l-carboxylic acid.
  • EXAMPLE V l-arnino 3 cyclopentene l carboxylic acid (4.4 g., 0.0346 mole), as prepared in Example IV, is stirred in 100 ml. of dioxane at 80 C. while phosgene is bubbled in for three hours. Thereafter, the reaction is flushed with dry nitrogen for one and one-half hours and the dioxane removed in vacuo. The residual oil is dissolved in ethyl acetate and crystallized with hexane to afford 3- oxa-1-azaspiro[4,4] non-7-ene-2,4-dione (yield 4.1 g., 77%), Ml. 133-5 C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US777506A 1968-11-20 1968-11-20 Cyclopentene derivatives Expired - Lifetime US3594413A (en)

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US (1) US3594413A (de)
BR (1) BR6914340D0 (de)
CH (1) CH556326A (de)
PH (1) PH9285A (de)
ZA (1) ZA697692B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001526A1 (en) * 1995-06-29 1997-01-16 Eli Lilly And Company Preparation of bicyclohexane derivative

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001526A1 (en) * 1995-06-29 1997-01-16 Eli Lilly And Company Preparation of bicyclohexane derivative
US5726320A (en) * 1995-06-29 1998-03-10 Eli Lilly And Company Preparation of bicyclohexane derivative
AU700608B2 (en) * 1995-06-29 1999-01-07 Eli Lilly And Company Preparation of bicyclohexane derivative

Also Published As

Publication number Publication date
BR6914340D0 (pt) 1973-02-22
ZA697692B (en) 1971-06-30
PH9285A (en) 1975-08-13
CH556326A (de) 1974-11-29

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